1-(paramethoxyphenyl)-2-formylaminopropanes and method of preparing same



. [nated connection. with the above general Patented Aug. 20, 1935 PATENT OFFICE AlVIINOPROPANES AND METHOD OF PREPARING SAME v Gordon A Alles, Monterey lark, Calif.

No Drawing.

Applicationk March13,1934; i Serial No. 715,314

1 iici ims. (organ-i249 This invention relates to a-new' and useful chemical compound 1-(paramethOXyphenylI-Z- formyla'minopropane;and its derivatives, having the general; formula j I V oH3o o6H4-oH2-ori oHnsumciio) of preparing compoundsjhaving the type formula above expressed, from paramethoxybenzyl methyl ketone (CH30-C6H4-CH2-COCH3)-, and one or more compounds comprising the corresponding amine, RNH2, and formic acid, the R in the amine formula having thesame significance as desigtype ,formula. Production of' l-(paramethoxyphenyl) -2'-formylaminopropanes has been carriedjout with good yields, by the method ofthe present invention, whereR; was: a L i The 'formylaminopropanes; of the present invention have some degree of physiological activity, but are particularly useful as intermediates for. the production of;-isoqu.inoline derivatives, and also for the production of; l-(parahydroxyphenyl)-2-aminopropanes having the general and their salts, which are physiologically active and produce eifects in animals and mansimilar to those produced by tyramine and its salts.

A. principalobject-of the present. invention is toprovide'a' new chemical compound l-(para- 'methoxyphenyl) 2 g formylaminopropane, and derivatives thereof, having the general type ill'WhiOh R is selectedfrom the group above-'- mentioned. V

Another principal object of the inventionis to provide a synthetic method of production of 1- (parainethoXyphenyl) 2 iormylaminopropanes of the above general'formula, which may be simply carried out with good yield;

. "The synthesis of these l-(paramethoxyphenyl) -2-formylaminopropanes may-be carried.

outwith variousstarting materials but common to all is the reaction between paramethoxybenzyl methyl ketoneand one or more compounds comprising an amine and formic acid, either alone or in the presence of some other substance. 5

' The actual starting materials used may comprise paramethoxybenzyl methyl ketone, together 7 with either: l

, (a). An amineformate;

'(b). An amine, and' formic acid or a formate; 10 (c). A saltof an amine, and formic acid or a formate.

1: Thus, four preferable combinations and proportions for carrying out the reaction are as follows:

- (1) The ketone and the amine formate. with the latter usually in excess of two molsper mol of ketone;

(2) The ketone, the amine, and formic acid,

with the latterusually in excess of two mols per mol of ketone and the-amine in amount equal or m excess of one mol per mol of ketone;

3) The ketone, a salt of the amine, and formic acid, with each of the lattertwo materials usually in excess of two mols per mol of ketone; or, (4) The ketoneQa salt of the amine,and sodium formate, with the latter two in equal molamounts and usually each in amounts up to two mols per mol of ketone.

The water resulting from the condensationreactions involved, or any excess formic or other acid present, serves" as a solvent which aids in promoting a smooth reaction between those substances desired to react. The reaction may be i usually carried out without using a closed reaction vessel, but better yields are commonly obtained when using a pressure autoclave with close control of the temperatures used for conducting the reaction. p

The synthesis may be carried out with good yield in accordance with any one of the following 40 specific procedures: 3

1) One mol of paramethoxybenzyl methyl ketone andiour mols of ammonium formate are mixed and heated together preferably in a flask I fitted with a reflux condenser, for a suitable pe- 'riod'such as forsix hours, maintaining the temperature between and C. After 0001- ing, the product may be mixed with some water and the water insoluble layer that separates may be removed and distilled under reduced pressure. 50 The fraction boiling between and 205 0. under a'pressure of 6 mm. of mercury is separated -and consists substantially entirely of l-(paramethoxyphenyl) -2 formylaminopropane', suitableior use in the synthetic production of other 5 45 o 3 hydrolysis under suitable] conditions it yields compounds. This productgives analyses cor're ladditionsalt, melting at 22390;

sponding to V I CH3OVC6H4CH2- C'H (CI-I3) NI-I -CHO; 1 It may be used, for example, to produce l-(para methoxyphenyl) 2-aminopropane by" hydrolysis thereof with alcoholic caustic' soda solution or constant boilin'g hydrochloric acid. The prodnot thus obtained may 'beidentifi'ed the form "of its hydrochloric acid addition salt;whi'ch melts I at 203 to 20510. L (2) One "mol of paramethoxybenzyl methyl ketone and one molrof ,ben zylaminej are;mixed with two mols of ninety'percent formic acid and" I heated together, preferably in a, flask fitted a reflux condenser, fora suitable period such "as? six' hours, maintaining the temperature between 115 and 130 C. The product maybe mixed-with! water and. the.Water-insoluble layer thatsenarates may be'remoyed, consisting substantially? of xcrude 1-(paramethoxyphenyllfieiiormylhen -z'y1aminopropane, which isisuitable ior' use;,in the synthetic production of other compounds. ;F,or example, hydrolysis thereofjwith constant ,lboila o ing; hydrochloric acid yields, 1- (paramethoxyphenyll-Z-benzylaminopropane which ymayf'be identified: inthe' form of: its-hydrochloric acid;

(3). One mol' of paramethoxybensyl methyl ketone and four; mols of ,annnonium acetate are mixed'with two mole-of ninety percent formic l acid and heated together with stirring, prefer- I ably, in 'jajrhigh pressure autoclave, maintaining the temperatureabout 1{l0-,C. fora suitable period or, ioriexamplegthree to; four hours iThe contents of the autoclave are mixed 'with ben- :zene, the benzene extract k separated;- and'i-the ,benzene then: removed Joy distillation; The residue is, distilled under reduced pressure and yields a large iraction boiling-betwennlilog and 200%; C. under-pressureifrom 6 to 10 'of -me rcury, co is quite pur -;,(pa am th yp 2 -iormyla,n'iinopropan e.v This product may also be used in thep roduction of other compounds.-

For, veiranriple, when subjected 1 toacid; or alkali l- (paramethoxyphenyl) -2-aminopropane which may be identified in the form of its hydrochloric acid addition salts l (4). One mol of fparamethoxybenzyl methyl ,ketone, one mol of -methy1amine hydrochloride, .one mol of, sodium formate' ,and over angel of aninetyper jcent formic'acidl are mixed and heated gtogether, preferably ina fiask fitted with ajre'fiux condenser for 'a suitable 1 period, such as six hours; maintaining the temperature between and 3 -C-; Theiprod v' fm d w a er and the insoluble layer that separates-istaken upwith ether. The ether extract maybe freed of ether Icy-distillation an dutheresiduel distilled suitable"v for i use I in the synthetic production .of other compounds. vcF013;exarnplj hydrolysis thereof L with; constant boiling ihydrochloric acid Y fi ,afte1i suitable manipulation, ousman; -oxyphenyl)-2-methy1aminopropane which may be identified in the for mof' its hydrochloric acid of "other compounds, For 1.examp-le; hydrolysis thereof with constant boiling hydrochloric acid yields, after suitable manipulation, l-(paramethv oxyphenyl) -Z-ethylaminopropane, which may be identified "n the-"form of -its hydrochloric acid additionflsaltl'melting' at 154 to 155 C.

paring I ;-l paramethoxyphenyl)ez-iormylaminm 'Iiieaboye. specific examples of methods or prepropanes according to the present' invention' are illustrativeof aitype reaction' in which an amine '-.'ianolgf6rmic acid are'caused tojreact with a. particularstarting material, namely, paramethoxybeiizyhmethyl ketone, In the first specific exkalifsaltio'f formic acidi and in the fifth. example the reaction is carried outijwithfanotheia alkyl .20 darn-ple the saidketoneiisreacted with a compound 'ajm neain theji'orm' of'an acidaddition salt, and e "formic acid,introducedentirely as an alkali salt, 'in jwhi'ch case the liberation offormicacid'forrejactionf with theibasejketon s efiectedjb'y' the acidicnatureof the amine compound}: It will be comprehended thatthe alcove exam les definitely illustrate that the" process :maypej carried out by ,re' g the" t in etbne i' t 'alre 'c mbina tion"whichbontains or yields b'iot ian arnine V and acid; where; R1 represents any "one of a number or selectedside radicals such as yielding formic'ac'id and an amine? (or yielding c mmand-aria ammonia or'other specific memberQrsubdiiiision of the general group'of amines) f is intended'to coyer any compound or mixture of comp d wh c ith mom s id onnic' acid a n 'ell sue g r w ch i atla tedzie he [presence of g the spccific ketone to yield such formic and amine y 1- (paramethoxyphenyl) -2 formylaminopi'opane,' haying the. foraa o o in which ,Riisfan alkyl'radical. a

ir'i'whichRis an aralkylradical.

' 3.{A chemicalicompoundassetfor-thin claiml, V

- 4, Afchemical Icompound as set forth in clainrql,

- phenyl) -2-formylaminopropanes having the general type formula which comprises: reacting paramethoxybenzyl methyl ketone with a reactive combination yielding; formic acid and an amine RNI-Iz, R designating hydrogen, an alkyl radical, or an aralkyl I radical. 10.

r 6. The method which comprises; reacting paramethoxyhenzyl methyl ketone with a reactive combination yielding ammonia and formic acid.

I. The method set forth in claim 6, said reactive 1 d combination comprising ammonium formate.

8. The method set forth in claim 6, said reactive combination comprising formic acid and a eral type formula salt of ammonia. V r V 9. Themethod of preparing l-(paramethoxyphenyl) -2-formylaminopropanes having the genin which R designates an alkyl radical, which V of preparing l-(paramethoxyphenyl)-2-formylaminopropane having the formula phenyl) -2-formylaminopropanes having the general type formula in which R designates an aralkyl radical, which comprises: reacting paramethoxybenzyl methyl ketone with a reactive combination yielding an aralkyl amine and formic acid.

12. The method of preparing l-(pararnethoxyphenyl-2-formylaminopropanes having the general type formula which comprises: reacting paramethoxybenzyl methyl ketone with an amine formate of the general formula RNHzHCOOH, R. designating hydrogen, an alkyl radical or an aralkyl radical.

13. The method of preparing l-(paramethoxyphenyl) -2-formylaminopropanes having the general type formula CH30CsH4-CH2CH (CH3) NR (CI-I) which comprises: reacting paramethoxybenzyl methyl ketone, a salt of an amine RNHz, and

formic acid, R designating hydrogen, an alkyl radical or an aralkyl radical.

14. The method of preparing l-(paramethoxyphenyl) -2-formylaminopropanes having the general type formula which comprises: reacting paramethoxybenzyl methyl ketone, a salt of an amine RNHz, and a salt of formic acid,'R designating hydrogen, an alkyl radical or an aralkyl radical.

GORDON A. ALLES. 

